Network Activity Shapes Inhibitory Synaptic Development in the Mouse Hippocampus.

The proper development of excitatory/inhibitory balance is critical for brain function, as any imbalance has been associated with myriad neuropsychiatric disorders. How this balance evolves during synaptic development remains unclear. To address this question, we examine how manipulations of SIRPα, a cell-adhesion molecule that organizes excitatory synaptic development in the hippocampus, affect inhibitory synaptogenesis to maintain excitatory/inhibitory balance, using mice of either sex. SIRPα primarily localizes to excitatory synapses. Overexpression or inactivation of SIRPα in a single neuron in hippocampal cultures affects excitatory, but not inhibitory synapses formed onto the SIRPα-manipulated neuron, indicating that SIRPα is an excitatory, but not inhibitory, synapse organizer. Despite this, bath application of SIRPα's ectodomain increases inhibitory synapses in culture, and global inactivation of SIRPα and during critical periods functionally decreases both excitatory and inhibitory synapses in the hippocampus. By using various conditional KO mice, we found that SIRPα from pyramidal neurons, but not from inhibitory interneurons, astrocytes, or microglia is necessary for proper inhibitory synapse development. Interestingly, inactivation of SIRPα from most pyramidal neurons is necessary to impact inhibitory synaptic development, suggesting that inhibitory synaptogenesis in the hippocampus is driven by the strength of excitation in the pyramidal-neuron network, and not by a change in excitatory input to a single cell. Consistently, the effect of SIRPα's ectodomain on inhibitory, but not excitatory synaptogenesis is blocked by global neural activity inhibition. We propose that the development of inhibitory synapses in the hippocampus is regulated by network-level excitatory activity to evolve excitatory/inhibitory balance. How excitatory/inhibitory (E/I) balance evolves during development is still unknown. We manipulated an excitatory synapse organizing cell-adhesion molecule, SIRPα, in the hippocampus and examined how inhibitory synaptogenesis is affected to maintain E/I balance. Global inactivation of SIRPα during a critical period functionally decreases both excitatory and inhibitory synapses. Using many mouse mutants and manipulations, we identified that inactivation of SIRPα from most pyramidal neurons is necessary to impact inhibitory synaptogenesis and that the effect of SIRPα on inhibitory synaptogenesis is blocked by global neural activity inhibition. Therefore, we propose that inhibitory synaptogenesis is regulated by the excitatory drive at the network level and not at the single-cell level. Our work reveals a fundamental mechanism that develops E/I balance.